In the techniques of nuclear magnetic resonance (NMR), a magnetic field acts on the nuclei of atoms with fractional spin quantum numbers and polarizes them into alignment within some selected orientations. During measurements, radio-frequency pulses of given resonance energy are applied that flip the nuclear spins and disturb the orientation distribution; then the nuclei returns (relax) to the initial state in a time dependent exponential fashion, thus giving signals which are electronically processed into recordable data. When the signals are spacially differentiated and of sufficient level, the data can be organized and displayed as images on a screen. For instance, computing the signals generated by the protons (.sup.1 H) of the water in contact with organic tissues enables to construct images (MRI) allowing direct visualization of internal organs in living beings. This is therefore a powerful tool in diagnosis, medical treatment, and surgery.
Despite the weakness of .sup.1 H natural polarization (6.8.times.10.sup.-6), but due to relative abundance of water in organic tissues, hydrogen nuclei will provide sufficient signal to be processed into images of an organ under investigation, the contrasts therein being provided by the differences in spin relaxation for the protons in contact with different portions of said organ. Indeed, although compounds containing fluorine (spin 1/2) have been investigated as NMR signal generators in the detection of gases in subjects, only water protons have been regularly used until recently to produce MRI images. This is so because the abundance of other organic atoms with nuclear spin, i.e. some naturally occurring isotopes of phosphorus (.sup.31 P), carbon (.sup.13 C), sodium (.sup.23 Na), sulfur, etc., is much too low to provide workable imaging signals.
Recently, it has been proposed to use in the MRI of patients isotopes of some noble gases in hyperpolarized form, e.g. .sup.3 He, .sup.129 Xe, .sup.131 Xe, .sup.83 Kr, and the like. Indeed, although the signal from these isotopes in the naturally polarized state is extraordinarily weak (actually 5000 times weaker than from .sup.1 H), hyperpolarization will effectively raise it about 10.sup.4 to 10.sup.5 times. Furthermore, the spin relaxation parameters of the hyperpolarized gases are very strongly influenced by the nature of the environment in which they distribute after administration (i.e. they provide a detailed array of signals of different intensities), which makes them very interesting contrast agents in MR imaging.
Hyperpolarizing noble gases is usually achieved by spin-exchange interactions with optically excited alkali metals in the presence or in the absence of an externally applied magnetic field (see for instance G. D. Cates et al., Phys. Rev. A 45 (1992), 4631; M. A. Bouchiat et al. Phys. Rev. Lett. 5 (1960), 373; X. Zeng et al., Phys. Rev. A 31 (1985), 260). With such techniques, polarization of 90% or more is possible, the normal relaxations (T.sub.1, T.sub.2) being so long (from several minutes to days in the case of Xe ice) that subsequent manipulations (use for diagnostic purposes) are quite possible. Otherwise, hyperpolarization can be achieved by metastability exchange, for instance by exciting .sup.3 He to the 2.sup.3 S.sub.1 state by radio pulses, optically pumping with 1.08 .mu.m circularly polarized laser light to the 2.sup.3 P metastable state and transferring polarization to the ground state by metastability exchange collisions with the ground state atoms (see L. D. Schaerer, Phys. Lett. 180 (1969), 83; F. Laloe et al., AIP Conf. Proc. #131 (Workshop on Polarized 3He Beams and Targets, 1984).
WO 95/27438 discloses use of hyperpolarized gases in diagnostic MRI. For instance, after having been externally hyperpolarized, the gases can be administered to living subjects in gaseous or liquid form, either alone or in combination with inert or active components. Administration can be effected by inhalation or direct intravenous injection of blood which is extracorporally contacted with the gas and reintroducing the contacted blood into the body. Upon administration, the distribution of the gas within the space of interest in the subject is determined by NMR, and a computed visual representation of said distribution is displayed by usual means. No practical example of administration of a parental contrast agent composition or formulation, nor identification of the additional components is provided.
U.S. Pat. No. 4,586,511 discloses administering organic fluorinated compounds to living subjects and effecting NMR measurements including chemical shifts, relaxation times, or spin-spin couplings. MRI is not mentioned.
In an article by H. Middleton et al., Mag. Res. Med. 33 (1995), 271, there is disclosed introducing polarized .sup.3 He into the lungs of dead guinea-pigs and thereafter producing an MR image of said lungs.
P. Bachert and al. Mag. Res. Med. 36 (1996), 192 disclose making MR images of the lungs of human patients after the latter inhaled hyperpolarized .sup.3 He.
M. S. Chawla et al. (Abstract of the Meeting on MRI Techniques Vancouver 1997) suggested using .sup.3 He microbubble suspensions in an aqueous saline carrier for MR vascular imaging. To stabilize the bubbles against buoyancy, Chawla et al. recommended to incorporate 40% PEG (Mw 3,350) to the carrier liquid. The bubbles were generated by injecting the gas with a syringe into the liquid via a three-way stopcock. MRI measurements were effected in vitro; no in vivo experiments are reported.
Although the suggestion of Chawla et al. is of interest, due to considerable bubble instability it could not be considered for practical applications. Despite using bubble stabilizers recommended by Chawla et al., suspensions in a carrier liquid of microbubbles of rare gases prepared according to the suggestion by authors collapsed in a matter of seconds under no or moderate external pressure. The fact that Chawla et al. microbubbles are so unstable makes them useless from the practical point and of no interest for use in vivo, i.e. for diagnostic applications in patients.